Synergistic compositions consisting essentially of combinations of active agents selected from oridonin, wogonin, and isoliquiritigenin for the prevention of neoplasia

Abstract

The present invention relates to the treatment of therapy-resistant neoplasias. The compounds and methods of the invention are particularly useful for the treatment of taxol-resistant human cancers, particularly cervical and breast cancer. Components of the compositions of the present invention show strong synergy with one another allowing them to be used in relatively low amounts for the treatment of stage IV or recurrent cancer which may have grown resistant to the traditional chemotherapeutic agents. These compositions comprise oridonin.

The invention claimed is: 
     
       1. A method of reducing cell proliferation in an individual having neoplasia, wherein the method consists essentially of administering to the individual synergistically effective combinations, with respect to one another, selected from the group consisting of:
 i) a compound having the structure of Formula I; 
 
       
         
           
           
               
               
           
         
         its pharmaceutically acceptable salts and esters, selectively substituted analogues, or a combination of one or more of the foregoing compounds together with 
         a compound having the structure of Formula II; 
       
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen, C 1 -C 6  alkyl; R 2  is hydrogen, C 1 -C 6  alkyl, or C 2 -C 6  acyl; and R 3 -R 10  are independently hydrogen, hydroxy, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or C 2 -C 6  acyl, with the proviso that at least four of R 3 -R 10  are hydrogen, its pharmaceutically acceptable salts and esters, selectively substituted analogues, or a combination of one or more of the foregoing compounds; 
         ii) the compound having the structure of Formula I, its pharmaceutically acceptable salts and esters, selectively substituted analogues, or a combination of one or more of the foregoing compounds and a compound having the structure of Formula IV 
       
       
         
           
           
               
               
           
         
         wherein R 11 -R 13  are independently hydrogen or C 1 -C 6  alkyl; and R 14 -R 20  are independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or C 2 -C 6  acyl, with the proviso that at least three of R 14 -R 20  are hydrogen, its pharmaceutically acceptable salts and esters, selectively substituted analogues, or a combination of one or more of the foregoing compounds; and 
         iii) a compound of Formula II its pharmaceutically acceptable salts and esters, selectively substituted analogues, or a combination of one or more of the foregoing compounds and Formula IV, its pharmaceutically acceptable salts and esters, selectively substituted analogues, or a combination of one or more of the foregoing compounds, 
         and wherein for the combinations ii) and iii) the neoplasia is a chemotherapy resistant neoplasia. 
       
     
     
       2. The method of  claim 1  wherein the neoplasia to be treated is prostate cancer, breast cancer, endometrial cancer, colon cancer, lung cancer, bladder cancer, testicular cancer, ovarian cancer, thyroid cancer or bone cancer. 
     
     
       3. The method of  claim 1  wherein the neoplasia to be treated is taxol-resistant ovarian or breast cancer. 
     
     
       4. The method of  claim 1  wherein the compound having the structure of Formula II is substituted so that R 1  is methyl, R 2  is hydrogen, and R 3 -R 10  are independently hydrogen, methyl, ethyl, methoxy, ethoxy, acetyl, or propionyl, with the proviso that at least five of R 3 -R 10  are hydrogen. 
     
     
       5. The method of  claim 4  wherein the compound having the structure of formula II is substituted so that it has the structure of Formula III 
       
         
           
           
               
               
           
         
       
     
     
       6. The method of  claim 1  wherein the compound having the structure of Formula IV is substituted so that R 11  -R 13  are hydrogen and R 14 -R 20  are independently hydrogen, methyl, ethyl, methoxy, ethoxy, acetyl, or propionyl, with the proviso that at least four of R 14 -R 20  are hydrogen. 
     
     
       7. The method of  claim 6  wherein the compound having the structure of formula IV is substituted so that it has the structure of Formula V 
       
         
           
           
               
               
           
         
       
     
     
       8. The method of  claim 1  wherein compounds according to Formulae I, II, and IV are obtained from extracts. 
     
     
       9. The method of  claim 1 , wherein combination iii) is administered, wherein the compound having the structure of formula II is substituted so that it has the structure of Formula III, and wherein the compound having the structure of formula IV is substituted so that it has the structure of Formula V.